Process for the manufacture of allopregnanes



United States Patent 3,026,336 PROCESS FOR THE MANUFACTURE OFALLOPREGNANES Albert Wettstein, Riehen, and Karl Heusler, Basel,

Switzerland, assignors to Ciba Pharmaceutical Prodnets Inc, Summit, NJ.N0 Drawing. Filed Dec. 23, 1959, Ser. No. 861,447 Claims priority,application Switzerland Dec. 24, 1958 6 Claims. (Cl. 260397.4)

The present invention provides a process for the manufacture of16a-alkyl-l7a-hydroxy-allopregnane-ZO-ones from A -pregnadiene-20-ones,and is concerned more especially with the selective hydrogenation of the5 :6- double bond in 20enol acylates of A -16a-alkyl-pregnene-20-ones.The 16a-alkyl-l7a-hydroxy-allopregnane- 20-ones are importantintermediates for the synthesis of corticosteroids containing al6a-alkyl radical such, for example, asl6a-methy1-9u-fluoro-prednisolone and prednisone, as well as of1Got-methyl-17a-hydroxy-progesterone, and of esters of these compounds.

Among the pregnane compounds used industrially for the manufacture ofcorticoid hormones, the M -3,8- hydroxy-20-oxo-pregnadiene (l6dehydro-pregnenolone) obtained from diosgenin, and its esters, are ofspecial importance owing to their ready accessibility.

That is the reason why said compound has been used as starting materialin the synthesis of the highly active l6a-methyl-9u-fluoro-prednisolone.In the first stages of this synthesis lfi-dehydro-pregnenolone acetateis reacted with methyl-magnesium iodide to yield l6a-methyl-pregnenoloneacetate; the 5:6-double bond is then hydrogenated, the 20-enol acetateis prepared and oxidised with peracid; and the resulting20-acetoxy-l7z20-epoxide is hydrolysed to form 3 3:17a-dihydroxy-16u-rnethyl-a1lopregnane- 20-one. The yields obtained inthis process-both in the introduction of the l6a-methyl group and moreespecially in the preparation of the 20-enol acetate-amount only toabout 40 to 60%, and the isolation of by-products and starting materialis difficult and requires in most cases chromatographic operations.

The present invention is based on the observation that the conversion of16-dehydro-pregnenolone and of its esters to3,8:l7a-dihydr0xy-l6a-alkyl-allopregnane-20-one can be carried out witha high yield and by way of a uniform reaction when a A-35:20-diacyloxy-l6a-alkylpregnadiene, prepared fromlfi-dehydro-pregnenolone or from an ester thereof, is hydrogenated inthe presence of a noble metal catalyst, the hydrogenation product istreated with an organic per-acid and the resulting oxidation product ishydrolysed.

The A 3:ZO-diacyloxy-loa-alkyl-pregnadienes used as starting materialsare obtained from 16-dehydro-pregnenolone or a 3-ester thereof by theprocess described in our patent application Serial No. 845,078 filedOctober 8, 1959, by Albert Wettstein et al. in a yield of 90 to 95%.According to that process l6-dehydro-pregnenolone or a 3-ester thereofis reacted with an alkyl-metal compound, preferably withmethyl-magnesium iodide, and the metal enolate thus formed is treatedwith an acylating agent. The 3:20-diacylates contain in positions 3 and20 two identical or two difierent acyl groups derived from aliphatic,araliphatic, aromatic or heterocyclic carboxylic acids, such as lowerfatty acids, for example formic acid, acetic acid, propionic acid,butyric acid, valeric acid, caproic acid, oenanthic acid, caprylic acid,phenylacetic acid, para-nitrophenylacetic acid, benzoic acid,paramethoxybenzoic acid, 2:4:6-tribromo-benzoic acid, orfuran-2-carboxylic acid.

It is surprising that in these A -3:2O-diacyloxyl6a-alkyl-pregnadienesthe 5 :6-double bond is easy to by- 3,026,336 Patented Mar. 20, 1962 icedrogenate selectively, and a high yield of the correspondingallopregnenes is obtained without attack upon the enol double bond. Theselective hydrogenation is advantageously performed with a noble metalcatalyst, more especially palladium in the form of palladium carbon oron a support such as calcium carbonate, strontium carbonate, bariumsulfate, zinc oxide or animal carbon, in an inert solvent such as analcohol, for example methanol, ethanol, propanol, or in an ether such astetrahydrofuran or dioxane. The calculated amount of hydrogen is takenup even at room temperature and under atmospheric pressure within ashort time, which can be shortened by adding a small proportion of anacid, such as perchloric, oxalic or other acids. The hydrogenated enolacetate can in many cases be obtained in crystalline form.

The oxidation of the hydrogenated enol acetate is carried out in an assuch known manner with an organic per-acid, for example with peracetic,perbenzoic or monoperphthalic acid. It has, however, been observed thatthe oxidation of the 16a-alkyl compounds progresses muchmore slowly thanthat of the 16-unsubstituted 20-enol The epoxides formed can behydrolysed with; acid or with alkaline agents, for example with dilutesulacylates.

Example 1 1.0 gram of a crystalline mixture of the two 20-isomeric A-3,8:2O-diacetoxy-16a-methyl-pregnadienes is dissolved in 30 cc oftetrahydrofuran, treated with mg. of 10% palladium carbon catalyst and50 mg. of oxalic acid, and stirred under hydrogen at 30 C. After 8 hoursthe amount of hydrogen calculated for 1 molecular equivalent has beentaken up. 0.5 cc. of pyridine is added, the catalyst is filtered oil andrinsed with methylene chloride, and the filtrate is evaporated todryness in a water-jet vacuum. The residue (1.14 grams) consists of amixture of the two 20-isomeric A-3B:20-diacetoxy-16amethyl-allopregnenes.

960 mg. of this crude enol acetate are dissolved in 4.0 cc. of molarethereal monoperphthalic acid solution and maintained for 2 days at 25C. The solution is then diluted with 60 cc. of ether, the etherealsolution is washed with sodium bicarbonate solution and water, dried andevaporated in a water-jet vacuum.

The residue (1.30 grams) crystallizes on addition of a small amount ofmethanol; it is dissolved in 40 cc. of methanol, treated with a solutionof 500 mg. of potassium carbonate in 10 cc. of water, and the whole isrefluxed for 2 hours, then cooled, treated with 60 cc. of water andsuction-filtered. After drying, 716 mg. of pure35:17adihydroxy-16a-methyl-allopregnane-20-one are obtained.

Example 2 A solution of 10 grams of the crystalline mixture of the twoZO-isomeric A -3p:20-diacet0xy 16a methyl pregnadienes in 200 cc. ofrectified spirit is treated with 1.0 gram of 10% palladium carboncatalyst and agitated for 8 hours under hydrogen, after which time theabsorption of hydrogen ceases almost completely. The catalyst issuctioned off, the filter residue is rinsed with methylene chloride, andthe filtrate evaporated to dryness in a waterjet vacuum.

The crude hydrogenation product is dissolved in 40 cc. of molar etherealmonoperphthalic acid solution and kept for 3 days at 25 C., during whichtime phthalic acid separates in colorless crystals. The whole is dilutedwith 200 cc. of ether, the ethereal solution is decanted from theprecipitate, Washed with sodium bicarbonate solution and Water, driedand evaporated to dryness.

The residue is dissolved in 400 cc. of methanol, treated with a solutionof 5.0 grams of potassium carbonate in 100 cc. of water, and refluxedfor 2 hours under nitrogen. The reaction product begins to crystalliseafter a short time. After lapse of the reaction time, 300 cc. of Waterare added, the whole is allowed to cool and then suctionfiltered, toyield an almost pure crude product melting at 226230 C. Byrecrystallization from methanol a total of 6.90 grams of pure318:17a-dihydroXy-16a-methyl-allopregnane-ZO-one, melting at 232-235 C.,is obtained in two fractions. Yield: 82% of theory.

In a completely analogous manner 3flzl7a-dihydroxy-.16a-methyl-allopregnane-20-one (melting at 232235 C.) is obtained fromA -3B:20-dipropionyloxy-16amethyl-pregnadiene in a yield of 85%, andfrom A 3,6-capryloXy-20 acetoxy-1tie-methyl pregnadiene in a yield of80%.

What is claimed is:

1. Process for the manufacture of 3fizl7a-dihydroxy- 16oc-1OW61alkyl-allopregnane-ZO-ones, wherein a M 3Z20-difiCY1OXY-16u-1OW6I'alkyl-pregnadiene is hydrogenated in the presence of a palladiumcatalyst, the hydrogenation product is treated with an organic peracidand the resulting oxidation product hydrolysed.

2. Process as claimed in claim 1, wherein a M3:20-diacyloxy-lfia-methyl-pregnadiene is used as starting ReferencesCited in the tile of this patent UNITED STATES PATENTS 2,783,252Schmidt-Theme Feb. 26, 1957 2,786,856 Cutler et a1 Mar. 26, 19572,794,034 Ruschig et a1 May 28, 1957 OTHER REFERENCES Olivcto et 2.1.:80 IACS, 4431 (1958).

1. PROCESS FOR THE MANUFACTURE OF 3B:17A-DIHYDROXY16A-LOWER ALKYL-ALLOPREGNANE-20-ONES, WHEREIN A $5:17(20)3:20-DIACYLOXY-16A-LOWER ALKYL-PREGNADIENE IS HYDROGENATED IN THE PRESENCE OF A PALLADIUM CATALYST, THE HYDROGENATION PRODUCT IS TREATED WITH AN ORGANIC PERACID AND THE RESULTING OXIDATION PRODUCT HYDROLYSED. 